Search

Background: Antitubulin agents exhibit antiangiogenic effects in vitro and in vivo. We evaluated the safety and feasibility of administering a metronomic schedule of oral vinorelbine designed to optimize its antiangiogenic effects. Methods: Patient with advanced cancer who had progressive disease after standard therapy received oral vinorelbine 3 times weekly (i.e., Monday, Wednesday, Friday) at the 6 dose levels ranging from 20 mg (1 week on, 1 week off) to 50 mg (3 weeks on, 1 week off) in cohorts of 3-6 patients at each dose level using a standard phase I design. Dose-limiting toxicity (DLT) during cycle 1 included: (1) neutrophil nadir < 500/μL attributed to therapy, (2) platelet nadir < 50,000/μL attributed to therapy, (3) grade 3-4 non-hematologic toxicity attributed to therapy, and (4) neutropenia associated with grade 2 fever (i.e., febrile neutropenia). Results: Nineteen patients received 50 cycles of therapy (range 1-11 cycles) at 6 dose levels. There were no dose-limiting toxic events. There were no consistent changes in serum TIE-2 or VCAM-1 levels, or urinary VEGF. One patient with renal cell carcinoma had stable disease for 9 months, and another patient with metastatic prostate cancer had a 70% decline in serum prostate-specific antigen, which lasted 4 months. Conclusions: Oral vinorelbine may be given using a metronomic schedule, 50 mg thrice weekly for three of 4 weeks, with minimal toxicity in patients with advanced cancer. [ABSTRACT FROM AUTHOR]

The article presents a study on the impact of high-sensitivity C-reactive protein (hsCRP) to maternal diet and outcomes of pregnancy. HsCrp is said to be a biomarker for the inflammatory process at entry to care. It is said that the highest tertile of hsCRP is relevant to the increased risks for early delivery. The study concludes that high hsCRP is a diet-related biomarker for the poor pregnancy outcomes among lean women with normal glucose tolerance.

Abstract: Objective: To identify adverse risk factors for FIGO IA1 and IA2 cervical adenocarcinoma. Methods: PubMed was used to identify all microinvasive adenocarcinoma cases. Case specific data pooled for 35 “high risk” microinvasive adenocarcinoma (MIAC), defined as cases with lymph node or lymphovascular space involvement, positive surgical margins, or recurrence was compared with 478 “low risk” cases abstracted from the SEER database (1988–1997). Statistical methods included non-paired t and Fisher''s Exact tests. Results: Survival for 1A1 and 1A2 MIAC is 99% and 98%, respectively. Significantly more 1A2 patients underwent aggressive radical surgery and received postoperative treatment. Parametrial involvement was rare (1/373 cases). Significantly more “high-risk” cases were of endometrioid histology (6/34 vs. 14/478, p =0.001), whereas adenocarcinoma (p =0.046) and mucinous (p =0.021) tumors were observed in the “low-risk” group. Among the “high-risk” cases with at least 5years follow-up, 1.4% has recurred or died. Conclusions: Endometrioid histology may be associated with late recurrence and worse survival in stage 1A1 and 1A2 MIAC. [Copyright &y& Elsevier]

Serum CA125 is a potential biomarker for metastatic disease and recurrence in patients with uterine papillary serous carcinoma (UPSC).All patients with UPSC who had preoperative CA125 measurement and surgical staging between 1998 and 2008 at the participating institutions were included in this analysis (N = 52). Data were extracted from patients' records. Fisher exact and χ2 tests were used to assess the association of CA125 levels with clinical and pathological variables. The correlation between CA125 levels (high/low) and lymph node metastases (positive/negative) was evaluated using Spearman correlation coefficients. The association of CA125 elevation with recurrence-free survival was assessed using Cox proportional hazards regression modeling.Preoperative CA125 elevation (>30 U/mL) was observed in 9 (17%) patients and was associated with advanced International Federation of Gynecologists and Obstetricians (FIGO) stage III/IV disease (P = 0.002), lymph node involvement (P = 0.007), and presence of omental metastases (P = 0.001). Disease recurrence and survival data were available for 51 of the 52 patients. During a mean follow-up time of 36 months, 15 (29%) patients experienced disease recurrence and 10 (19%) patients died. There was a moderate positive correlation between CA125 levels and lymph node metastases (r2 = 0.39). On multivariate survival analysis, an elevated CA125 level compared to nonelevated CA-125 was not associated with disease recurrence (hazard ratio, 1.61; 95% confidence interval, 0.55-4.77).Preoperative CA125 levels were significantly associated with metastatic disease in patients with UPSC. However, in this study of surgically staged UPSC patients, preoperative CA125 elevation was not an independent predictor of disease recurrence. [ABSTRACT FROM AUTHOR]

This issue of Topics in Stroke Rehabilitation explores the theme of medical phenomenology and stroke rehabilitation through open peer commentary format. The theme is introduced by a brief summary and overview of phenomenology as a branch of philosophy whose focus is the development of methodology for describing and ordering human experience. The application of this philosophical approach to medicine in general and stroke rehabilitation in particular is then considered. An approach to patients informed by both phenomenology and science provides a more complete, holistic, and humanistic framework than science alone. Phenomenology helps the clinician to understand the importance of narrative, the process of adaptation at the level of the integrated whole person, and the important role of context in determining how recovery unfolds. Embodiment is presented as an organizing principle that links the nature of conscious experience in the lived body and the basic transformation in experience and function associated with an acquired pathology such as stroke. Finally, the nature of open peer commentary is considered and introduced in terms of how it has been specifically implemented in this issue of Topics in Stroke Rehabilitation. [ABSTRACT FROM AUTHOR]

Integrin-mediated activation of Cdc42 is essential for cell polarization, whereas the integrin adaptor protein Cas is required for cell migration during wound healing. After phosphorylation on tyrosine residues, Cas recruits the adaptor proteins Crk and Nck to execute integrin-mediated signals. However, the mechanisms leading to Cdc42 activation and its relationship with Cas, Crk and Nck have not been elucidated clearly. In the present study, we demonstrate that Cas utilizes Nck2 to activate Cdc42 and induce cell polarization in response to wounding. By contrast, Cas recruits CrkII to activate Rac1 and promote the extension of cell protrusions needed for cell motility. These results indicate that Cas utilizes Nck2 and CrkII in a coordinated set of distinct pathways leading to cell migration. Structured digital abstract • : Cas (uniprotkb: ) and Nck2 (uniprotkb: ) colocalize ( ) by fluorescence microscopy ( ) [ABSTRACT FROM AUTHOR]

Burkitt’s lymphoma is extremely rare in the United States, with reports of approximately 300 new cases each year. A case of Burkitt’s lymphoma involving the uterus, cervix, ovaries and appendix 15 years after adjuvant chemotherapy for breast cancer is presented. A 58-year-old woman presented with an abdominal mass. MRI revealed a pelvic mass originating from the uterus. Her past medical history was significant for an infiltrating ductal carcinoma of the left breast with positive lymph nodes and extra nodal invasion diagnosed at age 43. She had a left modified radical mastectomy in 1990 with adjuvant chemotherapy. Histologic sections of the uterus, cervix, ovaries, appendix and external iliac lymph node obtained at laparotomy revealed diffuse neoplastic lymphoid infiltration with necrosis. Light microscopy revealed starry sky patterns and immunohistochemical staining demonstrated atypical lymphocytes which stained for CD20, CD10, bcl-6, and Ki-67. After complete staging, chemotherapy was started and the patient is presently tumor free 41 months after the diagnosis. Burkitt’s lymphoma arising from the uterus/cervix is extremely rare and may present as a pelvic mass. Early diagnosis, aggressive chemotherapy, ±surgical intervention, plays an important role in management and survival of patients with Burkitt’s lymphoma. [ABSTRACT FROM AUTHOR]

A conference paper about the efficacy of radioimmunotherapy (RIT) which targets E6 viral oncoprotein in the treatment of cervical cancer in mice is presented. It discusses the therapy of human papillomavirus type 16 (HPV-16) positive CasKi cells in vitro with external radiation, proteasome inhibitor MG-132, and unlabeled anti-E6 antibody C1P5. It concludes that pretreatment of cervical tumors with MG-132 and unlabeled antibody to E6 generated increased cell death of nonviable cancer cells.

The Src tyrosine kinase associates with the focal adhesion adaptor protein Cas (Crk-associated substrate) to suppress the expression of potential tumor suppressor genes. For example, Src utilizes Cas to suppress the expression of the LIM-only protein Fhl1 (four and a half LIM domains 1), in order to promote non-anchored tumor-cell growth and migration. Here, we report that the promoter region of the Fhl1 gene was methylated more in Src-transformed cells than non-transformed cells. In addition, global expression analysis indicates that Fhl1 induced expression of serum deprivation response factor (Sdpr) in Src-transformed cells. Moreover, Fhl1 and Sdpr was expressed in approximately 87% and 40% of samples obtained from non-transformed breast, 100% of samples obtained from non-transformed kidney, and over 60% of samples obtained from non-transformed prostate. In contrast, Fhl1 and Sdpr was detected in approximately 40% and 7% of matched samples from mammary carcinoma, less than 11% of matched samples from kidney carcinoma, and in less than 22% of matched samples from prostate carcinoma. These data indicate that Fhl1 and Sdpr expression was significantly reduced in tumors of the breast ( P < 0.02 and P < 0.001), kidney ( P < 0.01), and prostate ( P < 0.05). In addition, although Src can activate mitogen-activated protein kinase (MAPK) to promote tumor-cell growth, our data indicate that Src did not rely on MAPK activity to suppress the expression of Fhl1 and Sdpr in transformed cells. Thus, Src induced methylation of the promoter region of the Fhl1 gene; Src suppressed Fhl1 and Sdpr expression independent of mitogen-activated protein kinase (MAPK) activity; Fhl1 induced the expression of Sdpr in Src-transformed cells; and Fhl1 and Sdpr expression was suppressed in tumors of the breast, kidney, and prostate. ( Cancer Sci 2008; 99: 1326–1333) [ABSTRACT FROM AUTHOR]

Background: Struma ovarii is a rare monodermal ovarian teratoma composed predominantly of mature thyroid tissue. Of these cases, 5–8% are clinically hyperthyroid and 5–10% of these tumors are malignant. Case Report: A 53-year-old female presented with a 19 × 5 × 5 cm pelvic mass that was treated with bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node sampling, omentectomy and appendectomy and staging for an ovarian tumor. There was no evidence of distant metastases or lymph node invasion. Re-evaluation of the patient after surgery revealed that she was clinically euthyroid and there was no thyroid malignancy. Histopathology revealed papillary thyroid carcinoma arising in struma ovarii (malignant struma ovarii). Conclusion: Malignant struma ovarii is a very rare malignant ovarian teratoma. In young patients unilateral oophorectomy and complete surgical staging should be considered when the tumor is confined to the one ovary (stage Ia). Long-term follow-up for the detection of metastases or tumor recurrence by serial serum thyroglobulin and 131I scan or positron emission tomography/computed tomography may be required in selected patients with this rare tumor. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background and Objective: Preclinical data suggest gemcitabine may have schedule-dependent activity favoring prolonged infusion. We sought to determine the recommended phase II dose (RPTD) and toxicity of gemcitabine when given as a continuous intravenous (CIVI) over 96 h.Patients and Methods: Gemcitabine was initially given at 1 mg/m(2)/d for 48, then 72, and finally 96 h. The dose was then increased to 2, 4, 6, 10, 15, 20, and 25 mg/m(2)/d. Dose levels of 7, 8, 9 mg/m(2)/d as 96-h infusion were added later after a protocol modification. After identifying the RPTD using an every 3-wk schedule, we then evaluated the feasibility of repeating the infusion every 2 wk, and then weekly for 3 of 4 wk.Results: Thirty-four patients with a variety of tumor types received a total of 126 cycles of therapy (median of 2 cycles, range 1-10 cycles). The RPTD was 8 mg/m(2)/d every 3 wk, and 6 mg/m(2)/d every 2 wk. The most common grade 2 or higher toxicities at all dose levels (>or= grade 2) included fever (n = 14), dyspnea (n = 7), mucositis (n = 6), hypotension (n = 6), nausea/vomiting (n = 6), and fatigue (n = 5). Neutropenia and/or thrombocytopenia were uncommon.Conclusion: Administration of gemcitabine as a 96-h infusion results in a markedly different toxicity profile and RPTD than when given by a conventional 30-min infusion. The RPTD was 8 mg/m(2)/d (32 mg/m(2)/course) when given every 3 wk, or 6 mg/m(2)/d (24 mg/m(2)/course) when given every 2 wk. [ABSTRACT FROM AUTHOR]

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

Nontransformed cells form heterotypic cadherin junctions with adjacent transformed cells to inhibit tumor cell growth and motility. Transformed cells must override this form of growth control, called "contact normalization", to invade and metastasize during cancer progression. Heterocellular cadherin junctions between transformed and nontransformed cells are needed for this process. However, specific mechanisms downstream of cadherin signaling have not been clearly elucidated. Here, we utilized a β-catenin reporter construct to determine if contact normalization affects Wnt signaling in transformed cells. β-catenin driven GFP expression in Src transformed mouse embryonic cells was decreased when cultured with cadherin competent nontransformed cells compared to transformed cells cultured with themselves, but not when cultured with cadherin deficient nontransformed cells. We also utilized a layered culture system to investigate the effects of oncogenic transformation and contact normalization on gene expression and oncogenic Src kinase mediated phosphorylation events. RNA-Seq analysis found that cadherin dependent contact normalization inhibited the expression of 22 transcripts that were induced by Src transformation, and increased the expression of 78 transcripts that were suppressed by Src transformation. Phosphoproteomic analysis of cells expressing a temperature sensitive Src kinase construct found that contact normalization decreased phosphorylation of 10 proteins on tyrosine residues that were phosphorylated within 1 h of Src kinase activation in transformed cells. Taken together, these results indicate that cadherin dependent contact normalization inhibits Wnt signaling to regulate oncogenic kinase activity and gene expression, particularly PDPN expression, in transformed cells in order to control tumor progression. [ABSTRACT FROM AUTHOR]

Reports on the preliminary Phase II clinical and pharmacokinetic study of 9-cis retinoic acid in advanced cervical cancer. Demographic characteristics; Toxicities; Pharmacokinetic parameters for 9-cis and other retinoids.

A case of ovarian Sertoli-Leydig cell tumour with a raised serum alpha fetoprotein in reported. The patient first presented at the age of 27 years with a history of 6 years' amenorrhoea followed by 3 months irregular vaginal bleeding. A ovarian tumour was found and excised and shown microscopically to be a spindle cell malignant tumour. The patient was treated with chemotherapy and had a complete response. Thirty months after first presentation there was a recurrence in the pelvis which microscopically showed the typical features of a Sertoli-Leydig cell tumour. Six months later a second recurrence had the microscopic appearance of a lipid cell tumour. A raised serum alpha fetoprotein was found at the time of the second recurrence and immunohistochemistry showed this protein in the Leydig and luteinized cells of the recurrent tumours but not in the spindle cells of the original ovarian neoplasm. [ABSTRACT FROM AUTHOR]